Inflammation is a normal response of the organism to infection, injury, and trauma. Within the brain, a complex series of immune-like reactions is initiated to neutralize invading pathogens, repair injured tissues, and promote wound healing to restore tissue homeostasis. While neuroinflammation has been considered a mediator of secondary damage, the local immune response also has beneficial effects on the traumatized tissue. Such effects include the clearance of cellular debris, secretion of neurotrophic factors, cytokines, and activation of proteases for matrix remodeling. Therefore, while inflammation in the brain can have negative effects on recovery following injury, other actions appear to be beneficial and essential (1). In this framework, inflammation can be viewed as a complicated series of local immune responses that serve to deal with a threat to the neuronal microenvironment. Both beneficial and adverse properties have been assigned to the pro-inflammatory cytokine TNF alpha; we have now characterized the unique relationships between neurons and microglia that influence these outcomes (2). With a targeted chemical-induced injury to the hippocampus we demonstrated a response heterogeneity in resident microglia by immunohistochemistry and level of TNF alpha as determined by laser capture microdissection and qPCR. In individual dentate granule neurons, internalization and temporal sequence of expression of TNFp55 receptor followed by TNFp75 receptor was associated with the progression of apoptosis. In protected CA1 pyramidal neurons, an upregulation of TNFR membrane expression was observed. Neuronal death was blocked by neutralizing antibodies to TNF alpha and in TNF receptor knockout mice. Damage was exacerbated in single TNF receptor knockout mice and TNFp75R-mediated apoptosis occurred in the absence of TNFp55R. This data showed a direct relationship between the microglia response, the level of TNF alpha, and receptor localization in determining neuronal death or survival. Thus, TNFR localization can serve as a critical marker for distinguishing the effects of TNF alpha in the brain. Often, interleukin-1 beta is considered the initial cytokine response leading to neuronal death and in regulating the microglia response. Using IL-1R knockout mice we demonstrated a delay in the microglia response to injury rather than the absence of a response previously reported in the literature. In addition, we confirmed that, for hippocampal dentate granule cells, activation of IL-1R1 is not required for cell death (3). [unreadable] [unreadable] Another role for microglia is in the clearance of excess or aberrant proteins in the brain, such as amyloid. A defective clearance of amyloid beta 42 in the brains of Alzheimers disease patients has been associated with decreased microglial, and possibly infiltrating macrophage, function to clear the excess protein. We have now demonstrated that raft aggregation and the formation of a phagocytic cup, using real-time imaging and immunohistofluorescence, are critical for amyloid beta-42 (Abeta42) mediated microglia phagocytosis (4). The phagocytic activity is stimulated with low doses of Abeta42 and inhibited with high dose levels. In addition, we demonstrated that a prolonged exposure to celecoxib disrupts rafts in a manner similar to that seen in an elevated Abeta42 environment resulting in an impaired recruitment of the scavenger receptor CD36 to rafts for phagocytosis. We are now translating these findings to determine if this is a generalized process for aberrant protein fragments and examining the microglia response to neurons expressing a mutated form of Huntingtin.[unreadable] [unreadable] The purpose of this project is to identify the critical features of the glia response that may either cause or exacerbate an ongoing process of neuronal death and how these features change with underlying chemical exposure, head trauma and stress as well as the immune system integrity, and life stage. We have reported that developmental exposure of non-human primates to lead (Pb) results in an amyloid-like pathology similar to that seen in Alzheimer's disease. One possible target for this pathology may a change in microglia/macrophage functioning as Pb is known to influence the immune system. Using genetically modified mice we are able to address questions with regards to genetic susceptibility for disease processes as well as specific modifications of the immune system and inflammatory response to injury. In addition to the impact of the immune cells on neuronal death, we are currently examining the role of neuroinflammation in the initiation and success of injury-induced adult neurogenesis and how this process may be altered as a function of age or environmental exposure.